A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiol's antidepressant efficacy in perimenopausal depression. Nonetheless, there is no direct evidence that estradiol withdrawal precipitates depressive episodes in those women who develop depression during the perimenopause. In these studies, first we examine the effects of estradiol withdrawal and the recent onset of hypogonadism on mood symptoms in asymptomatic premenopausal women. Second, we investigate what factors influence the development of depression during estradiol withdrawal. We administered a gonadotropin releasing hormone (GnRH) agonist for two to three months to 60 regular cycling, asymptomatic, healthy, premenopausal women (age - mean (SD) = 33.4 (8.1) years). Only three women (5.0% of the sample) reported clinically significant symptoms of depression. In contrast to the relative absence of depressive symptoms in these women, we did observe the significant appearance of several symptoms including hot flushes, disturbed sleep, and diminished libido. The latter finding is consistent with a prior study performed in a smaller subsample of these women in whom significant reductions in libido (as measured by a modified Derogatis Inventory of Sexual Functioning Scale) was observed in approximately 30% of the sample. Thus, in otherwise healthy women, the induction of neither hypogonadism nor hot flushes (with an accompanying sleep disturbance) uniformly precipitates depressive symptoms. In these studies, we also investigate two factors that could impact the appearance of depression during estradiol withdrawal - age and a previous episode of depression. We evaluate the effects of the acute withdrawal of estradiol therapy in older postmenopausal women with and those without a past perimenopausal depression. Preliminary results suggest that estradiol withdrawal induces depressive symptoms in women with a past perimenopausal depression, but not in those without such a history. In women with a past depression during the perimenopause, estradiol withdrawal is associated with a significant increase in depressive symptoms compared with those women who were maintained on estradiol therapy under double-blind conditions. Additionally, no significant depressive symptoms emerged in the women lacking a history of depression who were either withdrawn or maintained on estradiol therapy. Thus, in contrast to our findings with GnRH agonist-induced hypogonadism in premenopausal women with no past psychiatric history, estradiol withdrawal in women with a history of perimenopausal depression triggers mood symptoms. These data are consistent with those from epidemiologic studies showing that, for a subgroup of women, the endocrine events of the late menopause transition may represent important triggers for mood destabilization and the onset of depression. Both the markers of this risk and the mechanisms underlying estradiol withdrawal-induced depressive symptoms remain to be identified. Depressive symptoms emerged during estradiol withdrawal only in the older women with a past depression during the perimenopause, but not in either the younger or older women with no past depressions. Thus, during estradiol withdrawal, the ages of the women appear to be less of a contributor to the development of depressive symptoms than a past episode of depression. In a second ongoing study, we are investigating the impact of a past depression (not related to the perimenopause) on the effects of estradiol withdrawal on mood. Preliminary observations suggest that GnRH agonist-induced hypogonadism in asymptomatic premenopausal women with a past episode of depression is accompanied by the onset of depressive symptoms. If confirmed in a larger sample, these data suggest that in contrast to the effects of GnRH agonist-induced hypogonadism observed in asymptomatic premenopausal women with no history of depression, a single episode of depression (whether related to the perimenopause or not) could increase a womans susceptibility to develop negative mood symptoms during induced hypogonadism/estradiol withdrawal. The results of the Womens Health Initiative (WHI) have deterred many women from using estrogen therapy. Although considerable controversy exists regarding the applicability of the WHIs findings to younger perimenopausal women, many women and their physicians are concerned about the long-term risks of estrogen therapy. In a previous study, we demonstrated the antidepressant effects of the short-term administration of estradiol in women with perimenopausal depression. In an ongoing study, we now are examining the effects on mood and behavior of two compounds that for many women represent alternatives to traditional estrogen therapy. Specifically, selective estrogen receptor modulators (SERMs) and phytoestrogens (plant-derived estrogen-like compounds) have become available and are reported to display both tissue-specific profiles of estrogen agonist and antagonist actions and differential affinities from estradiol for the two forms of estrogen receptor. For many women, these novel compounds represent safer alternatives to estrogen therapy for the prevention of osteoporosis, and possibly, the treatment of perimenopausal symptoms. The use of SERMs and phytoestrogens may be preferred given their more favorable patterns of side effects, their lower risk of stimulating breast and endometrial cancers, and the perception that some of these compounds (phytoestrogens) are dietary supplements. Preliminary results demonstrate that after eight weeks of either estradiol or raloxifene, mood rating scores were significantly decreased compared with baseline scores and significantly lower than scores in women receiving placebo. Women receiving either phytoestrogen or placebo showed no significant improvement compared with their baseline scores. If confirmed in a larger sample of women, raloxifenes equal efficacy to that of estradiol would provide an alternative therapeutic option with a more acceptable profile of long-term side effects. In future studies, we intend to investigate the behavioral relevance of estrogen receptor beta in humans. Specifically, we will examine the antidepressant/anxiolytic efficacy of selective estrogen receptor beta agonists (when available for human use) in women with perimenopausal depression. These data will not only establish the role of estrogen receptor beta in the mechanism of estradiols antidepressant action, but could identify a promising new class of therapeutic agents that are safer and more acceptable than estrogen and potentially lack the side effects or withdrawal syndromes associated with traditional psychotropics. Finally, the comparison of the mood and behavioral effects of raloxifene and phytoestrogens to that of estradiol may allow more precise inferences to be made about the specific brain regions and estrogen receptor subtypes involved in estradiols antidepressant effects. Additionally, it is possible that the selectivity of these compounds for estrogen receptor alpha and beta may identify the mechanisms of efficacy of estradiol on specific target symptoms. Finally, as phytoestrogens are already commonly recommended, well accepted, and widely used for the treatment of mood symptoms, further clarification of their mood effects could have significant public health implications.